Inflammatory disorders of the eye have historically been recognized as complex and vision threatening. Although numerous pharmaceutical agents and compositions exist for its treatment, their side effects profile and effectiveness are less than desired. The side effects may not be acceptable in a particular patient, or if prolonged use is required. The current invention provides a new and original method for treatment of ocular inflammation.
Inflammation of the eye may be localized to the eye, the eyes, or may be part of more generalized inflammatory process. Its etiology may be infection, allergy, immunological reactions, or as a response to surgery, injury, or due to any other causes. The ocular inflammation causes pain, irritation, watering, threatens visual function of the eye and may also change optical properties of the eye. Inflammation may be seen as uveitis or keratoconjunctivitis.
Uveitis is an inflammation of the uvea, the middle layer of tissue behind the white of the eye. The cause of uveitis is poorly understood, but a variety of systemic diseases are associated with it. Uveitis has been treated by various classes of compounds including steroids and nonsteroidal anti-inflammatory agents such as dexamethasone, flurometholone, prednisolone, indomethacin, aspirin, flubiprofen and diclofenac. However, a number of uveitic cases are not responsive to or become refractory to these drugs. Kulkarni, P., 17(2) JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS 181–7 (2001). Serious side effects including cataract, glaucoma, delayed wound healing, and altered prostaglandin production, Id., at 181, and corneal complications including ulceration, perforation, and corneal and scleral melts have been reported with the use of topical nonsteroidal anti-inflammatory drugs. Guidera, A C, Luchs, J I, Udell, I J, 108 OPHTHALMOLOGY 936–944 (2001). Steroids are known to cause increased ocular pressure, cataracts, superinfections, and reduced immunity to infection. Olsen, E G & Davanger M, 62(6) ACTA OPHTALMOL 893–9 (1984).
A newer immunosuppressive, Tacrolimus, is used orally in uveitis, but may cause severe side effects similar to those seen with cyclosporin including renal dysfunction, and neurological disorders. Kulkarni, at 183. The use of Cyclosporin A is further limited by its low penetration into the eye. Van der Bijl, P, van Eyk, A D & Meyer, D 20(5) CORNEA 505–8, 505 (2001). Aldose reductase inhibitors have also been used, especially in diabetics. U.S. Pat. No. 4,600,717, to York. Fibronectin has also been tried to improve healing, but the defect closure rate was unaltered in the treated group. Phan, T M 30(3) Invest Ophthamol Vis Sci 377–385, 381 (1989).
Mast cell stabilizers such as topical Lodoxamide and Cromolyn Sodium have been used to treat vernal keratoconjunctivitis. Avunduk, A M, et al, 107 OPHTHALMOLOGY 1333–1337(2000). Nedrocromil sodium has a safety profile similar to cromolyn sodium. Verin P J, Dicker I D, Mortemousque B, 29(4) CLIN EXP ALLERGY 529–36 (1999). Vernal keratoconjunctivits is often controlled with topical steroids, but the vision threatening side effects are worse than the underlying disease, which usually is self-limiting and resolves as the patient grows up. Verin, 28(S6) ALLERGY 44—(1998)
Immunosuppressives such as topical Cyclosporin A have been used in the treatment of Mooren's ulcer, vernal keratoconjunctivitis, ulcerative keratitis associated with rheumatoid arthritis, anterior uveitis, and Thygeson's punctate keratitis. Kulkarni, P., 109 OPHTHALMOLOGY 845–850 (2002). Recurrence may occur in some patients. Field, A J, Gottsch, J D, 23(4) AUST N ZEALAND J OPHTHALMOLOGY 333–334 (1995). Cidofovir 1% has been used in acute adenoviral keratoconjunctivits but is limited by local toxicity including conjunctival injection chemiosis and punctate epithelial keratitis during the course of treatment and subepithelial infiltrates. It may cause an atypical and uncomfortable erythema of the skin of the eyelids and pronounced conjunctival injection that could be differentiated from adenoviral conjunctival inflammation alone. Hillenkamp, et al 109 OPHTHALMOLOGY 845–850, 847 (2002).
Researchers have studied the use of human epidermal growth factor on postkeratoplasty re-epithelialisation without success, in spite of promising earlier animal data no benefit on epithelial healing. Dellaert M J, et al, 81 BR J OPHTHALMOL 391–395 (1997).
Accordingly, a need exists for novel ophthalmic pharmaceutical compositions which safely and effectively treat ocular inflammation conditions.
It was disclosed that the 4-aminoquinolines have strong anti-inflammatory action and are useful for treatment of inflammatory diseases. Rynes, R I, 36 BR J RHEUMATOL 799–805 (1997). However, there has been no report or study in ophthalmologic field. The anti-inflammatory properties of the anti-malarial 4-aminoquinoline pharmaceuticals are well known. They have not been used to treat inflammation of the eye because their systemic use in high doses has been associated with a rare, but serious, incidence of ocular toxicity including corneal deposits known as verticillata, loss of foveal reflex, impairment of accommodation, maculopathy and retinopathy. These effects may be reversible or irreversible.
Retinopathy is the major and potentially most serious as it is irreversible. Jones, S K, 140(1) BRIT J DERMATOL 3–7, (1999). Ocular toxicity, however, is believed to occur only when doses exceed 6.5 mg/kg/day for a minimum of five (5) years. Cordes, M G, 2000 Southern J Optometry, Poster (2000). The dosage of chloroquine appears to be the most fundamentally important factor in determining the risk of development of retinopathy. In general, it appears that serious retinopathy in nearly all instances is caused by taking more than 250 mg of chloroquine diphosphate or 200 mg of chloroquine sulfate per day to a total amount greater than 100 gms. By not exceeding this daily dosage, it has been found possible for patients to take chloroquine for as long as nine years without developing clinically evident retinopathy. In most cases in which dosage slightly greater than 250 mg chloroquine diphosphate per day has been administered, the onset of definite retinopathy has taken one to three years. According to Nylander, most patients who have developed retinopathy have received nearly a total of 300 gms for three or more years. TOXICOLOGY OF THE EYE, Vol. 1, 272 (Grant, M., ed, 2nd Edition).
This inventor has discovered that when used directly in the eye, the 4-aminoquinoline compounds are non-toxic and highly effective in a wide variety of ocular inflammatory disorders. The 4-aminoquinoline compounds used here in novel ophthalmic pharmaceutical compositions have been previously reported to be useful as therapeutics in the treatment of malaria and rheumatoid arthritis. See, for example, U.S. Pat. No. 4,421,920 to Baudouin, U.S. Pat. No. 5,596,002, to Hofheinz, U.S. Pat. No. 5,948,791, also to Hofheinz.